bims-imseme Biomed News
on Immunosenescence and T cell metabolism
Issue of 2025–07–06
twenty-two papers selected by
Pierpaolo Ginefra, Ludwig Institute for Cancer Research



  1. Immunometabolism (Cobham). 2025 Jul;7(3): e00064
      The differentiation of naive CD8+ T cells into effector or memory populations requires dynamic remodeling of cellular metabolism and proteome composition. In a recent study published in Nature Immunology, Sinclair et al offer critical insights into the role of autophagy, particularly mitophagy, in regulating these processes during CD8+ T cell differentiation. Autophagy, a conserved catabolic mechanism, is traditionally associated with cellular homeostasis and survival during nutrient deprivation. In contrast, Sinclair et al reveal that, in the immune system, autophagy is not simply a survival mechanism but a fine-tuned regulator of CD8+ T cell metabolism and function, fine-tuning CD8+ T cell effector vs quiescence choices.
    Keywords:  CD8+ T cells; autophagy; cytotoxic T cell; mitophagy; naive T cells
    DOI:  https://doi.org/10.1097/IN9.0000000000000064
  2. Mol Cell. 2025 Jul 03. pii: S1097-2765(25)00462-9. [Epub ahead of print]85(13): 2455-2457
      In this issue of Molecular Cell, Zhou et al.1 show that glycogenolysis-derived glucose-1-phosphate enhances glucose-6-phosphate dehydrogenase oligomerization and activity, promoting the formation of a liquid-liquid phase separation compartment containing glycogen. This channels glycogenolysis-derived glucose-6-phosphate into the pentose phosphate pathway, supporting CD8+ memory T cell fitness and antitumor effects.
    DOI:  https://doi.org/10.1016/j.molcel.2025.05.023
  3. Cell Rep. 2025 Jul 01. pii: S2211-1247(25)00704-1. [Epub ahead of print]44(7): 115933
      Glycans are emerging as important regulators of T cell function but remain poorly characterized across the functionally distinct populations that exist in vivo. Here, we couple single-cell analysis technologies with soluble lectins and chemical probes to interrogate glycosylation patterns on major T cell populations across mouse and human tissues. Our analysis focused on terminal glycan epitopes with immunomodulatory functions, including sialoglycan ligands for Siglecs. We demonstrate that glycosylation patterns are diverse across the resting murine T cell repertoire and dynamically remodeled in response to stimulation. Surprisingly, we find that human T cell populations do not share the same glycoprofiles or glycan remodeling dynamics as their murine counterparts. We show that these differences can be explained by divergent regulation of glycan biosynthesis pathways between the species. These results highlight fundamental glycophysiological differences between mouse and human T cells and reveal features that are critical to consider for glycan-targeted therapies.
    Keywords:  CP: Cell biology; CP: Immunology; T cells; adaptive immunity; glycan biosynthesis; glycocalyx; glycosylation; sialic acid
    DOI:  https://doi.org/10.1016/j.celrep.2025.115933
  4. JHEP Rep. 2025 Jul;7(7): 101435
      
    Keywords:  CD8 T cells; Immunology; T helper cells; autoimmune disease; viral hepatitis
    DOI:  https://doi.org/10.1016/j.jhepr.2025.101435
  5. Life Metab. 2025 Aug;4(4): loaf018
      Circadian rhythms are fundamental regulators of physiological processes, including immune function. Recent insights uncover that not only lymphocytes but also myeloid cells possess intrinsic circadian clocks that govern their behavior and function. Emerging evidence highlights how circadian regulation of metabolism critically shapes the inflammatory and tissue-repair functions of myeloid subsets. Furthermore, mitochondrial dynamics, a key metabolic feature, are under circadian control and influence antigen presentation and effector functions. Here, we review the interplay between circadian clocks, metabolism, and myeloid immunity, discussing their therapeutic opportunities for optimizing vaccination, infection management, and immunotherapy.
    Keywords:  circadian rhythms; metabolism; myeloid cell
    DOI:  https://doi.org/10.1093/lifemeta/loaf018
  6. Adv Sci (Weinh). 2025 Jun 30. e01179
      T cell effector functions are critical for immune defense, but their dysregulation can cause diseases like immune exhaustion in cancer and loss of tolerance in autoimmunity. Curtailing these functions is essential in therapies such as chimeric antigen receptor T-cell (CAR-T) therapies or organ transplantation to avoid hyperactivation and rejection. A major challenge in the field is the precise, live measurement of T cell function at the single-cell level, limiting the prediction of immune responses, the development of effective immunotherapies, and optimization of immunosuppressive regimens. Gamma-Glutamyl Cysteine Ligase (GCL), the rate-limiting enzyme in glutathione (GSH) synthesis, is essential for T cell function in mice, but its role in human T cells is underexplored. GLed, a novel reversible lanthanide-based GSH sensor is introduced that enables real-time, quantitative measurements of GCL activity at single-cell resolution. The GLed approach distinguishes GSH contributions from GCL and GSR, linking GCL activity directly to human T cell effector functions. Additionally, this reveals previously unknown modulation of GCL activity by immunosuppressive drugs, underscoring GCL as a critical player in T cell function and a potential therapeutic target in immune-related diseases.
    Keywords:  T cells; glutamate‐cysteine ligase; glutathione; immunosuppression; lanthanide sensor
    DOI:  https://doi.org/10.1002/advs.202501179
  7. J Immunol. 2025 Jun 23. pii: vkaf093. [Epub ahead of print]
      Placentation presents immune conflict between mother and fetus, yet in normal pregnancy maternal immunity against infection is maintained without expense to fetal tolerance. This is believed to result from adaptations at the maternal-fetal interface (MFI), which affect T cell programming, but the identities (i.e. memory subsets and antigenic specificities) of T cells and the signals that mediate T cell fates and functions at the MFI remain poorly understood. We found intact recruitment programs as well as proinflammatory cytokine networks that can act on maternal T cells in an antigen-independent manner. These inflammatory signals elicit T cell expression of costimulatory receptors necessary for tissue retention, which can be engaged by local macrophages. Although proinflammatory molecules elicit T cell effector functions, we show that additional cytokine (transforming growth factor β1) and metabolite (kynurenine) networks may converge to tune T cell function to those of sentinels. Together, these data demonstrate that T cells at the MFI are broadly recruited and restrained in an antigen-independent, cytokine/metabolite-dependent manner. These mechanisms provide insight into antigen-nonspecific T cell regulation, especially in tissue microenvironments in which they are enriched.
    Keywords:  T cells; human; mucosa; reproductive immunology
    DOI:  https://doi.org/10.1093/jimmun/vkaf093
  8. Front Immunol. 2025 ;16 1560104
      Assays to monitor metabolic parameters of immune cells at a single cell level provide efficient means to study immunometabolism. We show here that staining intensity of mitochondria targeting probes in T cells is dramatically influenced by P-glycoprotein/P-gp expression, a xenobiotic efflux pump that extrudes these fluorescent dyes. Discrepancies between MitoTracker Green FM/MTG signals and multiple dye-independent measurements are seen in CD4 T and CD8 T cell subsets and are corrected by P-gp inhibition (PSC833) during MTG staining. We further investigate invariant Natural Killer T (iNKT) cells, which express the highest level of P-glycoprotein among T cells. Using mtDNA abundance, mitochondrial volume, respiration and proteomics, we establish that iNKT cells have higher mitochondrial content and activity than CD4 T cells, opposite to what MTG signals reveal. A similar phenomenon is also seen in human PBMCs, and with TMRE, a dye indicator of mitochondrial membrane potential. Collectively, these data argue that P-glycoprotein expression is a significant confounding factor when analyzing T cells using mitochondrial specific dyes. Complementary methods are necessary to reliably assess mitochondrial features in T cells.
    Keywords:  P-glycolprotein; T cells; TMRE; mitochondria; mitotracker; oxidative phosphorilation
    DOI:  https://doi.org/10.3389/fimmu.2025.1560104
  9. Nat Immunol. 2025 Jun 30.
      Chronic hepatitis B virus (HBV) infection is marked by dysfunctional HBV-specific CD8+ T cells, and restoring their effector activity is a major therapeutic goal. Here, we generated HBV-specific CD4+ T cell receptor transgenic mice to show that CD4+ effector T cells can prevent and reverse the CD8⁺ T cell dysfunction induced by hepatocellular priming. This rescue enhances antiviral CD8+ T cell function and suppresses viral replication. CD4+ T cell help occurs directly within the liver, independent of secondary lymphoid organs, and requires local antigen recognition. Kupffer cells, rather than dendritic cells, are the critical antigen-presenting platform. CD4+ T cells license Kupffer cells via CD40-CD40L interactions, triggering interleukin (IL)-12 and IL-27 production. IL-12 expands the CD4+ T cell pool, while IL-27 is essential for CD8+ T cell rescue. Exogenous IL-27 similarly restores HBV-specific CD8+ T cell function in mice and in T cells isolated from chronically infected patients. These findings identify IL-27 as a tractable immunotherapeutic target in chronic HBV infection.
    DOI:  https://doi.org/10.1038/s41590-025-02199-3
  10. Semin Liver Dis. 2025 Jul 04.
      Aging is characterized by the progressive deterioration of cell and tissue functions. The liver, which regulates metabolic homeostasis, detoxification, and immune responses, undergoes structural and functional changes with age. These include increasing genomic instability, telomere attrition, epigenetic alterations, loss of proteostasis, deregulated nutrient-sensing and intracellular communication, mitochondrial dysfunction, cell senescence, stem cell exhaustion, chronic inflammation, disabled macroautophagy, and dysbiosis. These alterations contribute to hepatocyte dysfunction, impaired regenerative responses, and fibrosis risk, which all exacerbate existing liver diseases. Senescence involves irreversible cell cycle arrest resulting in an inflammatory, senescence-associated secretory cell phenotype. Senescent hepatocytes, liver sinusoidal endothelial cells, hepatic stellate cells, and Kupffer cells accumulate in the aged liver, creating an inflammatory and fibrotic microenvironment that promotes tumorigenesis. As the burden of aging-related liver disease increases, therapeutic strategies targeting hepatic senescence have gained attention. We review these, along with the mechanisms and pathogenic effects of liver aging.
    DOI:  https://doi.org/10.1055/a-2637-2549
  11. Immun Ageing. 2025 Jul 03. 22(1): 27
       BACKGROUND: Cytomegalovirus (CMV) infection is one of the most common infections in humans, and CMV antigens are the major drivers of repetitive T-cell stimulation as a part of a well-adapted immune response in immunocompetent individuals. With higher age, the recurrent clonal expansion of CMV-specific T cells results in high frequencies of CMV-specific effector T cells. Further on, CMV seropositivity has been linked to an increased risk of developing cardiovascular diseases (CVD). Here we investigated the frequency and phenotype of CMV-specific T cells in the circulation of a population cohort of 650 individuals focusing on the age group over 60 years. Circulating immune cells of individuals carrying the HLA-A*02 allele were investigated (n = 302) applying MHC class I tetramers.
    RESULTS: We add to previous knowledge by showing that the frequency of CMVpp65-specific CD8+ T cells is associated with the total percentage and absolute counts of CD8+ and CD4+CD8+ double-positive T cells within leukocytes, and further with systolic blood pressure (SBP) and history of CVD. An investigation into the differentiation status of CMV-specific T cells revealed an association of higher age and increased frequencies of both TEM and CD27-expressing TEMRA cells. In contrast, higher CMV-IgG titers were found to be associated with TEM and CD27- TEMRA cell frequencies. SBP significantly correlated with CMV-specific effector CD8+ T cells, which was mostly reflected by CD27- TEMRA cells.
    CONCLUSIONS: Within the circulating CMV-specific T cell population, different effector T-cell subtypes were associated with age, serostatus and SBP. This suggests that it is not age or infection per se that render CMV-positive individuals susceptible to CVD, but rather the cellular immune response to CMV. Detailed immunophenotyping may identify individuals whose immune systems are strongly influenced by the response to CMV, leading to health consequences and impairing healthy aging.
    DOI:  https://doi.org/10.1186/s12979-025-00523-x
  12. Nat Commun. 2025 Jul 04. 16(1): 6170
      Hematopoietic stem cells (HSC) with multilineage potential are critical for T cell reconstitution after allogeneic hematopoietic cell transplantation (allo-HCT). The Kitlo HSC subset is enriched for multipotential precursors, but their T cell potential remains poorly characterized. Using a preclinical allo-HCT mouse model, we demonstrate that Kitlo HSCs provide superior thymic recovery and T cell reconstitution, resulting in improved immune responses to post-transplant infection. Kitlo HSCs with augmented bone marrow (BM) lymphopoiesis mitigate age-associated thymic alterations and enhance T cell recovery in middle-aged mice. Mechanistically, chromatin profiling reveals Kitlo HSCs exhibiting higher activity of lymphoid-specifying transcription factors, such as, ZBTB1. Zbtb1 deletion diminishes HSC engraftment and T cell potential; by contrast, reinstating Zbtb1 in megakaryocytic-biased Kithi HSCs rescues hematopoietic engraftment and T cell potential in vitro and in vivo. Furthermore, age-associated decline in Kitlo HSCs is associated with diminished T lymphopoietic potential in aged BM precursors; meanwhile, Kitlo HSCs in aged mice maintain enhanced lymphoid potential, but their per-cell capacity is diminished. Lastly, we observe an analogous human BM KITlo HSC subset with enhanced lymphoid potential. Our results thus uncover an age-related epigenetic regulation of lymphoid-competent Kitlo HSCs for T cell reconstitution.
    DOI:  https://doi.org/10.1038/s41467-025-61125-1
  13. Res Sq. 2025 Jun 12. pii: rs.3.rs-6787101. [Epub ahead of print]
      Rab4A, a small GTPase overexpressed in T cells of patients with systemic lupus erythematosus (SLE), has been shown to activate mechanistic target of rapamycin (mTOR) signaling, which promotes proinflammatory T cell development and predisposes to nephritis in SLE. In this study, we demonstrate that Rab4A facilitates the endocytic recycling and surface expression of CD38, which, in turn, triggers NAD+ depletion, activates mTOR complex 1, and suppresses interleukin-2 (IL-2) production in CD4+ T cells. Rab4A-driven CD38-mediated NAD+ depletion elicits the accumulation of nicotinamide and ADP-ribose and secondary depletion of cyclic ADP-ribose. Surprisingly, rapamycin further enhanced CD38 expression and reduced IL-2 secretion, suggesting that IL-2 depletion is mTOR-independent. Alternatively, Rab4A-driven upregulation of CD38 promoted STAT3 expression and its acetylation, as well as FOXO1 expression, which underlies IL-2 depletion in CD4+ T cells. These findings reveal a novel Rab4A-driven CD38 signaling axis that links receptor trafficking to proinflammatory metabolic pathways, providing new targets for treatment in SLE.
    Keywords:  CD38; CD4+ T cells; IL-2; NAD+; Rab4A; autoimmunity; endosome traffic; mTOR; metabolism; systemic lupus erythematosus
    DOI:  https://doi.org/10.21203/rs.3.rs-6787101/v1
  14. Nat Aging. 2025 Jun 30.
      Aged hematopoietic stem cells (HSCs) exhibit diminished self-renewal and myeloid-biased differentiation with a decline in hematopoiesis and adaptive immune function. However, the molecular regulation of this impaired function remains largely unknown. Here, through an in vivo CRISPR-Cas9-based screen, we uncovered clusterin (Clu) as a driver of biased differentiation. Clu is upregulated in aged HSCs, and its knockout diminishes biased differentiation. Clu promotes mitochondrial hyperfusion by interacting with Mfn2 in aged HSCs, and its ablation attenuates oxidative phosphorylation, improves mitophagy, and reverses myeloid-biased differentiation via the OXPHOS-p38-Cebpb axis. Transplantation of Clu-depleted aged HSCs into middle-aged mice results in balanced hematopoiesis and improved physical functions. Together, our data identify Clu as a critical regulator of aging-associated myeloid bias and reveal an Mfn2-OXPHOS-p38-Cebpb axis as the mechanism underlying how Clu upregulation in aged HSCs leads to myeloid-biased differentiation, providing a target for rejuvenation of aged hematopoietic and immune systems.
    DOI:  https://doi.org/10.1038/s43587-025-00908-z
  15. Mol Metab. 2025 Jun 26. pii: S2212-8778(25)00101-2. [Epub ahead of print] 102194
      Viral infection of cells leads to metabolic changes, but how viral infection changes whole-body and tissue metabolism in vivo has not been comprehensively studied. In particular, it is unknown how metabolism might be differentially affected by an acute infection that the immune system can successfully clear compared to a chronic persistent infection. Here we used metabolomics and isotope tracing to identify metabolic changes in mice infected with acute or chronic forms of lymphocytic choriomeningitis virus (LCMV) for three or eight days. Both types of infection alter metabolite levels in blood and tissues, including itaconate and thymidine. However, we observed more dramatic metabolite changes in the blood and tissues of mice with persisting LCMV infection compared to those infected with the acute viral strain. Isotope tracing revealed that the contribution of both glucose and glutamine to the tricarboxylic acid (TCA) cycle increase in the spleen, liver, and kidneys of mice infected with chronic LCMV, while acute LCMV only increases the contribution of glutamine to the TCA cycle in the spleen. We found that whole-body turnover of both glutamine and thymidine increase during acute and chronic infection, whereas whole-body glucose turnover was surprisingly unchanged. Activated T cells in vitro produce thymidine and virus-specific T cells ex vivo have increased thymidine levels, nominating T lymphocytes as the source of thymidine in LCMV infection. In sum, we provide comprehensive measurements of whole-body and tissue metabolism in acute and chronic viral infection, and identify altered thymidine metabolism as a marker of viral infection.
    Keywords:  Immunometabolism; Isotope tracing; Metabolomics; Tissue metabolism; Whole-body metabolism
    DOI:  https://doi.org/10.1016/j.molmet.2025.102194
  16. Nihon Yakurigaku Zasshi. 2025 ;160(4): 268-273
      Aging is a physiological process caused by various genetic and environmental factors. Recently, it has been proposed that the disturbance of the nutritional-metabolic sensing pathway is one of the aging characteristics. In particular, nicotinamide adenine dinucleotide (NAD+) plays an important role in this pathway and is considered the regulator of aging. NAD+ regulates an energy metabolism as a co-factor and is also involved in various biological processes including transcription, stress responses, DNA repair, inflammatory responses as well as post-transcriptional modifications, as a substrate for sirtuins, poly ADP-ribose polymerase (PARP), and CD38. With age, DNA damage and chronic inflammation increase in organs, resulting in overconsumption of NAD+ via PARP and CD38. The reduced NAD+ levels decrease the activity of sirtuins and PARPs and impair energy metabolism, ultimately leading to aging and aging-related diseases. However, the precise metabolism of NAD+ in vivo and the mechanism of how NAD+ regulates aging remain elusive. Moreover, the clinical application of NAD+ supplementation therapy is still under development. In this review, we overview the NAD+ metabolism and its relation to aging. In addition, we describe the current issue and perspective of NAD+ supplementation therapy to promote a healthy lifespan.
    DOI:  https://doi.org/10.1254/fpj.24072
  17. Nat Commun. 2025 Jul 01. 16(1): 5600
      In eukaryotic cells, reactive oxygen species (ROS) serve as crucial signaling components. ROS are potentially toxic, so constant adjustments are needed to maintain cellular health. Here we describe a single-cell, mass cytometry-based method that we call signaling network under redox stress profiling (SN-ROP) to monitor dynamic changes in redox-related pathways during redox stress. SN-ROP quantifies ROS transporters, enzymes, oxidative stress products and associated signaling pathways to provide information on cellular redox regulation. Applied to diverse cell types and conditions, SN-ROP reveals unique redox patterns and dynamics including coordinated shifts in CD8+ T cells upon antigen stimulation as well as variations in CAR-T cell persistence. Furthermore, SN-ROP analysis uncovers environmental factors such as hypoxia and T cell exhaustion for influencing redox balance, and also reveals distinct features in patients on hemodialysis. Our findings thus support the use of SN-ROP to elucidate intricate redox networks and their implications in immune cell function and disease.
    DOI:  https://doi.org/10.1038/s41467-025-60727-z
  18. Nihon Yakurigaku Zasshi. 2025 ;160(4): 256-260
      Aging serves as a risk factor for various age-associated disorders, such as cancer and type 2 diabetes. The study of aging is linked with metabolic research, due to the metabolic changes associated with aging. For example, chronic inflammation and the accumulation of DNA damages associated with aging lead to a decrease in NAD+ levels and mitochondrial dysfunction, resulting in cells becoming irreversibly cell cycle arrested, known as senescent cells. Senescent cells exhibit metabolic changes distinct from normal cells, along with distinct phenotypic characteristics, such as the senescence-associated secretory phenotypes (SASP), characterized by the excessive secretion of bioactive molecules such as inflammatory cytokines and chemokines. The accumulation of senescent cells has been observed in the pathology of age-related diseases, and their characteristics are thought to contribute to disease progression. Recent research has focused on the characteristics of senescent cells, such as their resistance to apoptosis, and aims to eliminate these cells from the body through pharmacological inhibition. Indeed, experimental evidence has demonstrated improvements in age-related phenotypes following the removal of senescent cells. Here, we review how age-related changes in cell metabolism induce cellular senescence, what are the metabolic characteristics of senescent cells, and how they affect the organism. Additionally, we also review our recent findings on the elimination of senescent cells by pharmacological inhibition of glutaminolysis rate-limiting enzyme GLS1, and outline the prospects for drug discovery targeting senescent cells.
    DOI:  https://doi.org/10.1254/fpj.24066
  19. Int Immunopharmacol. 2025 Jul 01. pii: S1567-5769(25)01145-2. [Epub ahead of print]162 115155
       BACKGROUND: Immune rejection remains a leading cause of graft loss following organ transplantation, with CD4+ T cells playing a central role in this process. The PI3K/AKT/mTOR signaling pathway is essential for the activation, proliferation, and metabolic reprogramming of CD4+ T cells, making it an attractive therapeutic target. However, the role of Idelalisib (ID), a selective PI3Kδ inhibitor, in transplant immunity remains underexplored.
    METHODS: Purified CD4+ T cells from the spleens of C57BL/6 mice were cultured with ID. Activation, proliferation, differentiation and survival were evaluated. A fully mismatched skin and heart transplantation model was used to assess ID's effects on rejection. Histopathology analysis and transcriptomic sequencing were performed.
    RESULTS: ID significantly suppressed CD4+ T cell activation, proliferation, and Th1 differentiation, while enhancing cell survival-contrasting with the pro-apoptotic effects observed with the mTOR inhibitor rapamycin (Rapa). In the skin and heart transplantation models, ID reduced acute rejection, extended graft survival, and decreased the proliferation of CD4+ T cells and B cells. Transcriptomic analysis revealed downregulation of genes involved in T cells activation and differentiation (e.g., Zap70, Stat4), as well as markers of glycolysis (e.g., Gapdh, Pfkm). Functional assays confirmed reduced glucose uptake and lactate production in ID-treated cells.
    CONCLUSIONS: ID uniquely modulates T cell responses through PI3Kδ inhibition, providing a distinct immunosuppressive mechanism from that of mTOR inhibitors. These findings highlight the therapeutic potential of ID in preventing transplant rejection and reveal a critical link between PI3K signaling and CD4+ T cell metabolism.
    Keywords:  Alloimmune response; CD4(+) T cells; Idelalisib; Transplant rejection
    DOI:  https://doi.org/10.1016/j.intimp.2025.115155
  20. Curr Opin Immunol. 2025 Jul 02. pii: S0952-7915(25)00076-7. [Epub ahead of print]95 102600
      Exhausted CD8+T cells (CD8+Tex), characterized by progressive dysfunction and sustained inhibitory receptor expression, emerge as a potential therapeutic target for autoimmune diseases. While Tex impairs antitumor immunity, the reduced autoreactivity prevents the functioning of pathogenic CD8⁺T cells, contrasting with broad immunosuppression from conventional therapies. This review oveviews Tex drivers - inhibitory receptor upregulation, metabolic reprogramming, cytokine signaling, and regulatory immune cells crosstalk. We also distinguished Tex from anergy and senescence, emphasizing its superiority in inducibility and reduced risks in autoimmune disease treatment. Therapeutic strategies to promote Tex, such as immune checkpoint agonists, TCR overactivation, metabolic modulation, mechanical stress, and regulatory cell engagement, are critically evaluated. Challenges include ensuring specificity, timing interventions preempting pathogenic T cell activation, and leveraging various advancements in drug delivery. By reframing exhaustion as a protective mechanism, this approach aims to shift treatment paradigms from symptom management to pathogenic circuit disruption, offering a roadmap for next-generation precision immunotherapies for autoimmune diseases.
    DOI:  https://doi.org/10.1016/j.coi.2025.102600
  21. Nat Commun. 2025 Jul 01. 16(1): 5818
      Activated immune cells infiltrate the vasculature during the pathophysiology of hypertension by establishing a vascular-immune interface that contributes to blood pressure dysregulation and organ failure. Many observations indicate a key role of CD8+ T cells in hypertension but mechanisms regulating their activation and interplay with the cardiovascular system are still unknown. In murine model, here we show that a specific member of the phosphoinositide-3-kinases (PI3K) family of lipid kinases, PI3Kγ, is a key intracellular signaling of CD8+ T cells activation and RANTES/CCL5 secretion in hypertension: CCL5-CCR5 signaling is crucial for the establishment of the vascular-immune interface in peripheral organs, lastly contributing to CD8+ tissue infiltration, organ dysfunction and blood pressure elevation. Our studies identify PI3Kγ as a booster of effector CD8+ T cell function, even in the absence of external stimuli. Lastly, an enhanced PI3Kγ signaling mediates the bystander activation of CD8+ T cells and proves effective in transferring the hypertensive phenotype between mice.
    DOI:  https://doi.org/10.1038/s41467-025-61009-4